The cellular and molecular pathways involved in the effects of pro-inflammatory and immunoregulatory cytokines and chemokines on regulating HIV replication, as well as the effect of HIV on the ability of CD4+ T cells to respond to certain cytokines were investigated. Levels of in vitro HIV replication in CD4+ peripheral blood mononuclear cells (PBMCs) from HIV-infected subjects was found to reflect the net regulatory effects of endogenous HIV-suppressing beta chemokines (MIP-1-alpha, MIP-1- beta, RANTES) and endogenous HIV-inducing pro-inflammatory cytokines (tumor necrosis factor-alpha [TNF-alpha], interleukin [IL]-1-beta). In addition, it was found that different cytokine conditions resulted in the selective replication of either endogenous macrophage (M) or T cell (T)-tropic viral strains in CD4+ PBMCs obtained from certain HIV-infected individuals in vitro. The cytokines utilized to promote the selective replication of different HIV strains act in part by modulating the expression of strain-specific HIV entry chemokine receptors. Analyses of the ability of various PBMC subsets to produce beta chemokines revealed that natural killer (NK) cells are able to produce high levels of beta-chemokines in vitro, particularly in response to IL-2 and IL-15, and that NK-derived beta-chemokines strongly inhibit macrophage-tropic HIV entry and replication in vitro. In addition, in vitro triggering NK lytic activity was associated with increased secretion of beta-chemokines. Analysis of the levels of mRNA and intracellular protein for beta-chemokines in various PBMC subsets immediately following isolation suggest that NK cells are likely an important source of beta-chemokines in vivo.